Effective molecules in COPD exhibit a long duration of action

The superiority of the once-daily dual bronchodilator therapy with UMEC/VI vs twice-daily glycopyrrolate/formoterol fumarate (GLY/FOR) in improving trough forced expiratory volume in 1 second (FEV₁) in COPD patients (difference, 87.2 mL; 97.5 percent confidence interval [CI], 117.0 to 57.4 mL; p<0.0001) demonstrates that a sufficiently potent molecule can achieve more effective bronchodilation even with less frequent administration. [Adv Ther 2019;36:2434-2449]

“UMEC/VI exhibits a duration of action that lasts well beyond 24 hours, which suggests greater reduction in exacerbations and improvement in lung function,” said Jones. “We can see a similar benefit with the once-daily ICS/LABA, FF/VI, which demonstrated sustained bronchodilation over 48 hours in asthma patients. Molecules such as FF were designed to offer high potency and to be metabolized quickly so as to reduce the risk of side effects in patients.” [Respir Med 2016;119:115-121; Br J Clin Pharmacol 2020, doi: 10.1111/bcp.14406]

Consistent benefits with once-daily triple therapy

The benefits of triple therapy with an ICS/LAMA/LABA regimen over dual therapy with an ICS/LABA or a LAMA/LABA regimen for patients with moderate-to-severe COPD were previously demonstrated in two randomized, controlled, phase III studies: IMPACT, comparing 52 weeks of once-daily FF/UMEC/VI with once-daily FF/VI and UMEC/VI; and ETHOS, comparing 52 weeks of twice-daily high-dose or low-dose budesonide (BUD)/GLY/FOR with twice-daily BUD/FOR and GLY/FOR. [N Engl J Med 2018;378:1671-1680; N Engl J Med 2020;383:35-48]

In the IMPACT study, triple therapy with FF/UMEC/VI significantly reduced the risk of moderate-to-severe exacerbations vs dual therapy with FF/VI or UMEC/VI. Adding a LAMA (ie, UMEC) to dual therapy with FF/VI reduced exacerbations by 15 percent (rate ratio [RR], 0.85; 95 percent CI, 0.80 to 0.90; p<0.001), while adding an ICS (ie, FF) to UMEC/VI reduced exacerbations by 25 percent (RR, 0.75; 95 percent CI, 0.70 to 0.81; p<0.001). [N Engl J Med 2018;378:1671-1680]

Similar benefits were seen in the ETHOS study. Treatment with high-dose BUD/GLY/FOR significantly reduced exacerbations by 13 percent vs BUD/FOR (RR, 0.87; 95 percent CI, 0.79 to 0.95; p=0.003) and by 24 percent vs GLY/FOR (RR, 0.76; 95 percent CI, 0.69 to 0.83; p<0.001). (Figure 1) [N Engl J Med 2020;383:35-48]

Additionally, these studies demonstrated significant benefits with triple therapy for reducing all-cause mortality (FF/UMEC/VI vs UMEC/VI: hazard ratio [HR], 0.72; 95 percent CI, 0.53 to 0.99; p=0.042) and hospitalizations due to severe exacerbations (FF/UMEC/VI vs UMEC/VI: RR, 0.66; 95 percent CI, 0.56 to 0.78; p<0.001) in COPD patients. (Figure 2) The reduction in all-cause mortality seen with FF/VI vs UMEC/VI (HR, 0.61; 95 percent CI, 0.40 to 0.93; p=0.02) further demonstrated the benefit of once-daily ICS use in patients with COPD. [N Engl J Med 2018;378:1671-1680; Am J Respir Crit Care Med 2020;201:1508-1516]

“There is a clear and consistent benefit with ICS therapy in reducing all-cause mortality and hospitalizations in patients with moderate-to-severe COPD,” said Jones. “However, we did not see the same benefits with triple therapy in the ETHOS study as we saw in IMPACT.”

“Data from ETHOS showed similar reductions in the rate of mild-to-moderate exacerbations with the high-dose and low-dose triple therapy combinations,” said Jones. (Figure 1) “However, we only saw significant reductions in all-cause mortality with high-dose BUD/GLY/FOR vs GLY/FOR [HR, 0.54; 95 percent CI, 0.34 to 0.87].”

“Moreover, in contrast to triple therapy with FF/UMEC/VI, high-dose BUD/GLY/FOR did not significantly reduce hospitalizations due to severe exacerbations vs GLY/FOR [RR, 0.84; 95 percent CI, 0.69 to 1.03], and did not appear to be associated with a reduction in respiratory or COPD-related deaths. We can only assume that these differences may be due to the difference in duration of action of a once-daily vs twice-daily ICS.” [N Engl J Med 2020;383:35-48]

Pneumonia risk with ICS: A class effect

Patients who received any ICS-containing therapy in the IMPACT and ETHOS studies were found to have an increased risk of pneumonia. Rates of pneumonia as an adverse event of special interest ranged from 5 percent with UMEC/VI to 8 percent with FF/UMEC/VI, and from 3.2 percent with GLY/FOR to 5.5 percent with high-dose BUD/FOR. [N Engl J Med 2018;378:1671-1680; N Engl J Med 2020;383:35-48]

“It’s important to note that although the rates of pneumonia were higher in the IMPACT study, the pneumonia rate with dual bronchodilator therapy in IMPACT was as high as the pneumonia rate with ICS-containing treatment in ETHOS,” said Jones. “A more appropriate comparison of ratios of pneumonia rates revealed a comparable 50- to 70-fold increased risk of pneumonia across all ICS-containing therapies relative to dual bronchodilator therapy.” (Figure 3)

“The risk of pneumonia is a class effect seen with all ICS, although the rates of pneumonia in ETHOS suggest a dose-harm relationship,” added Jones. “A higher dose of BUD may be associated with a higher risk of pneumonia in COPD patients.”

Effective delivery of triple therapy

An efficient delivery system that performs consistently and is easy to use is important in COPD treatment. The Ellipta dry powder inhaler, developed for delivery of once-daily therapies for COPD, has demonstrated consistent dose delivery in in vitro studies with flow rates as low as 30 L/min. [J Aerosol Med Pulm Drug Deliv 2015;28:474-485]

“Predicting whether patients can achieve adequate inspiratory flow is difficult, as previous studies have highlighted the weak relationship between FEV₁ and patients’ peak inspiratory flow rate [PIFR], noted Jones. [Am J Respir Crit Care Med 2020;201:A4302]

Using real-world spirometry data from COPD patients, researchers have shown that the majority of COPD patients in clinical practice (>99.7 percent) can achieve the PIFR of 30 L/min required for appropriate dose delivery by the Ellipta inhaler. [Am J Respir Crit Care Med 2020;201:A4050]

The efficacy of the Ellipta inhaler as a single delivery system for triple therapy vs multiple inhaler triple therapy (MITT) in COPD patients was demonstrated in the randomized, phase IV INTREPID study. Patients were randomized to receive once-daily FF/UMEC/VI delivered with the Ellipta inhaler for 24 weeks, or clinician’s choice of any ICS/LAMA/LABA combination delivered through multiple inhalers. [Am J Respir Crit Care Med 2020;201:A4313]

“In clinical practice, we saw that triple therapy delivered through a single inhaler significantly improved FEV₁ from baseline vs MITT [difference, 50 mL; 95 percent CI, 26 to 73; p<0.001],” said Jones. “Moreover, Ellipta was associated with a 31 percent greater chance of a clinically significant improvement in health status compared with MITT.” [Am J Respir Crit Care Med 2020;201:A4313]

Conclusion

“Overall, we have good evidence that supports the use of once-daily FF/UMEC/VI triple therapy delivered through the Ellipta inhaler for patients with moderate-to-severe COPD,” concluded Jones.